The present invention concerns a device for iontophoretic administration of drugs and more particularly to administration of drugs to the eye.
The introduction of various drugs to the cornea of the eye, for example, administration of antibiotics for the treatment of microbial keratitus, is a complicated procedure. Presently, the routine treatment of microbial keratitus (MK) includes topical administration of highly concentrated antibiotics every 30 to 60 minutes day and night for several days. It should be noted that the bioavailability of a drug when administered in eye drops is very low (less than 1% of the administered dose) due to continuous rinsing of the drug by the tears.
An alternative method of administration of drugs is, by subconjunctival injections of antibiotics several times a day into the eye. The injections require a physician, are very painful and may cause severe complications such as perforation of the globe and scarring of the conjunctiva. Systematic administration of antibiotics is not effective in a vascular cornea.
Thus, there has been a constant search for development of alternative delivery techniques for overcoming the existing problems of administration of drugs to the eye. Some encouraging studies indicate efficacy of use of contact lenses soaked with highly concentrated antibiotics. However, these lenses may not be tolerable by patients with MK who commonly have inflamed and swollen conjunctiva and eye lids. There also have been some trials with liposomes incorporated with medicaments and use of laser, but these trials did not gain significant clinical acceptance.
Iontophoreesis (INT) is a noninvasive method which allows penetration of high concentrations of ionized molecules, such as drugs, into the tissue with the help of an electric current. In the past this method was utilized for anesthesia, for myringectomy, for diagnostic sweat testing in patients with cystic fibrosis and for administration of vidarabine in cases of herpes simplex. The drugs administered were steroids, antibiotics, peptides and analgesics. In ophthalmology, iontophoresis had been experimentally used in several animal studies to evaluate its efficacy in concentrating the drugs into the cornea or the eye. Barza(1) showed that transscleral INT using solutions may induce bactericidal concentrations of gentamicin (for several hours) in the vitreous of the monkey eye. Furthermore, repeated Electro Retino Graphia (ERG) tests did not show damage to the retina. Similar studies in the rabbit eyes presented high concentrations of gentamicin, cefazoline and ticarcillin in the vitreous(2). Iontophoresis was also efficient for treatment of microbial endophthalmitis in the rabbit eye. It has been reported(3) that INT of tobramycin was more effective than topical administration of tobramycin for experimentally induced keratitus in the rabbit eye. INT of gentamicin via the cornea in aphakic rabbit eye revealed high levels of gentamicin in the vitreous. Finally, INT increased the penetration of ketaconazole (an antifungal drug) into the animals"" anterior chamber(4).
The major limitations of INT in all prior art reports and trials were in the use of drug solutions which required complicated design of instruments needed in order to keep the fluid drug solution in contact with the desired tissue during the process of the iontophoresis. Handling of fluids to ensure their contact with a desired tissue is tricky, since the fluids leak, and form bubbles that reduce the efficacy of ionthophoretic process.
Another approach to iontophoretic administration of drugs to the eye was described by Grossman, who reported that marked concentrations of gentamicin can be transferred into the rabbit comes by INT when the drug gentamicin was incorporated in soft agar gel (instead of in a liquid solution)(5,6). However, the use of agar has major limitations as follows: agar is a biologic material, so that each batch preparation of the agar results in slightly different products causing problems in the reproducibility of the drug administration; the shelf life of agar is very limited, it has to be kept in a refrigerated and moist environment rendering it impractical for prolonged storage; agar is fragile and requires expertise to be placed directly in contact with the ocular surface without breaking; and finally some of the agar material will always stay on the ocular surface, causing irritation, eye redness and inflammation.
It would have been highly desirable to provide a device for iontophoretic administration of drugs to the eye which would be easy to operate, safe and would minimize damage to the eye.
The present invention concerns a device for iontophoretic administration of charged drugs to the eye comprising:
an applicator formed with a receiving portion adapted for holding a replaceable hydrogel carrier loaded with said drug and allowing contact of the carrier with a surface of the eye;
an electric current generating element, for generating currents not higher than about 1000 xcexcAmp, being electrically coupled to the said receiving portion such that the current once generated passes through the hydrogel carrier in a direction essentially normal to said surface;
a timing element for activating the electrical current generating element for pre-set periods of time not exceeding 120 seconds; and
a switch for activating said timing device.
The device of the present invention is suitable for safe administration of iontophoretic drugs into the eye which do not exceed pre-set periods, and do not exceed maximum level of electric current. The device of the invention enables safe reproducible and repeated administration of drugs to the eye.
The term xe2x80x9ccharged drugsxe2x80x9d refers to drugs which may be a priori charged, to the drugs which become charged in a solution with which the hydrogel carrier is loaded, as well as to drugs which are initially not charged, but become charged in the presence of an electrical current.
Examples of commonly used charged drugs include antibiotics such as: gentamicin, tobramycin, vancomycin; antifungal drugs including: miconazole, ketoconazole; anti-inflammatory agents such as: ibuprofen and its derivatives; timolol; steroids; anti glaucoma agents such as: pilocarpine; anticancer agents such as mitomicin C, methotrexate and 5-FU which are delivered to treat cancer of the eye or cornea; local anesthetics which are delivered to the eye and to the conjuctiva to anesthetize the eye before a treatment or reduce pain, such as lidocaine, bupivacaine and benoxinate.
The term xe2x80x9ceyexe2x80x9d refers to the external regions of the eyes and includes the cornea, conjuctiva, sclera, eye lids and lid margins.
The device comprises an applicator having a receiving portion which can hold a replaceable hydrogel carrier, that is loaded with the drug. The applicator is in the form which allows contact of the carrier and the surface of the eye. The applicator may be held by a specific external fixing device, for example, during an operation to ensure its position, but preferably, for ease of operation it should be hand held. The applicator may form a separate component of the device of the invention, or alternatively, the whole device of the invention may be in the form of a single instrument wherein the applicator is an integral part thereof.
The applicator has a receiving portion, for example in the form of an indention, or in the shape of a half-circle ring for holding a replaceable hydrogel carrier which is loaded with the drug. Preferably the indention is conical or cylindrical to accommodate a hydrogel carrier having a corresponding shape. Typically, the applicator or the whole device (when applicator is integral with the device) is in the shape of an elongated rod where the receiving portion is at the end of the rod.
The device includes an electrical current generating element which can be battery operated or connected to an external AC power source, for the generation of currents which are not higher than about 1000 xcexcAmp. The electrical current generating element is positioned so that it is electrically coupled to said receiving portion. In operation, when a hydrogel carrier is fitted within the receiving portion, the electrical current generating element, generate currents that pass through the hydrogel in a direction substantially normal to the surface of the eye, thus causing the migration of charged drugs from the hydrogel carrier to the eye. both due to electrical field as well as due to diffusion. Preferably, the device should also comprise an electric control element which can control the level of the current passed into the gel to a pre-set current. For example, the physician may decide to apply a current of a specific level by properly adjusting the control element.
The device should also include a timing device for activating the electrical current generating element for pre-set periods of time not exceeding 120 seconds. Thus in operation, the physician or the patient itself, may choose a preset period of time, and a pre-set level of electric current (by adjusting the electric control element), and by mere activation of the switch, produce an electrical current of a fixed duration and level.
Where the device of the invention is battery operated, and the device is in the shape of an instrument having an applicator integral therewith, the device should also contain a recess for holding the battery.
The ground element of the device, may be in the form of a separate wire extending externally from the applicator, which can be in touch with any part of the patient""s body, preferably on his face, to serve as ground.
By another aspect, the present invention concerns a system for iontophoretic administration of drugs to the eyes, comprising a device as described above, and a drug loaded hydrogel carrier which carrier has a shape and size so as to be accommodated by the receiving portion of said device. For example, where the receiving portion is conical or cylindrical, the carrier is in the form of conic or cylindric disc, respectively, having a size which precisely matches that of the receiving portion. Where the receiving portion is in the shape of a half ring the carrier is in the shape of a round disc. Preferably, the calibration size of the carrier should be in the size range of 0.2 mm (for administration to small regions of the eye) to about 20 mm, (for example, for administration to the whole region of the eye in larger animals such as cattle).
It is also possible to produce a system for iontophoretic administration of the eye, wherein the receiving portion is adjustable, so it can receive various hydrogel carriers of various sizes, so that a single applicator is suitable for many sizes of hydrogel carriers, for example the receiving portion may include a ring with an adjustable diameter which holds the carrier.
By a third aspect, the invention concerns a hydrogel carrier for use in the above system, comprising a hydrogel material having at least 50% w/w water content; the hydrogel carrier being impregnated with the charged drug. Typically, the hydrogel carrier should be in the shape of a conical or cylindrical disc.
The hydrogel material that is suitable for this application should contain at least 50% w/w of water to allow free transport of the drug through the gel; it should be compatible with the eye; be inert to the loaded drug and safe at storage and during application should not release any unwanted small irritating/toxic molecules; stable during the life of the application; it should be physically and chemically stable in order to maintain its shape and size and its chemical and physical integrity; and generally should be comfortable in contact with the eye.
The hydrogel material is typically uncharged but may contain anionic (carboxylates) or cationic (amino groups) residues to enhance drug release upon application of a current pulse. The hydrogel may contain other organic or inorganic ions and salt solutions. Hydrogel discs are prepared from various known hydrogel compositions including: acrylic based hydrophilic monomers, crosslinked, polysaccharides and polyols, and crosslinked polyethylene glycols. Various compositions of hydrogels are described in the literature(7).
The charged drugs are loaded into the hydrogel carrier either during the preparation of the gel (for example during the polymerization process) or by placing a pre-prepared carrier pellet in a drug solution so that the gel absorbs the solution.
The present invention further concerns a method for the administration of charged drugs to the eye comprising:
(i) contacting a substance of the eye with a hydrogel carrier impregnated with said drug;
(ii) passing a current through said carrier at an intensity below about 1000 xcexcAmp for a period not exceeding 120 seconds and in a direction normal to said surface, thereby causing the charged drug to migrate from said carrier to the eye.
Preferably the method should make use of the system of the invention. The method is suitable for medicinal and veterinary purposes.
In the following, the invention will be further described with reference to some non-limiting drawings and examples.